Immediate hypersensitivity diseases, including asthma, hay fever, and allergic conjunctivitis are associated with a variety of unpleasant symptoms including tearing, inflammation, and breathing difficulty. The physiological mechanisms which promote these symptoms are similar for all hypersensitivity diseases and generally are initiated by environmental antigens. Patients suffering from the effects of hypersensitivity diseases are predisposed to specific external antigens. When these antigens contact certain tissues such as ocular, nasal, or lung tissues, these tissues become sensitized and produce undesirable and frequently life-threatening symptoms.
Allergic conjunctivitis in particular can be an extremely debilitating disease for children. While the response to allergic conjunctivitis may be limited to mild tearing and red-eyes, the much more severe form of vernal conjunctivitis is very common among children with this disease. Vernal conjunctivitis produces such serious responses as severely swollen eyelids, and extremely irritated and itching eyes to the point where it adversely effects the quality and the way of life of those having the disease. The discomfort is frequently so great that children suffering from the vernal conjunctivitis are unable to sleep or participate in school activities.
Traditionally, the preferred treatment for hypersensitivity diseases has involved the use of antihistamines. Unfortunately, antihistamines alone do not entirely abolish the adverse symptoms of these diseases and more efficacious forms of therapy are needed, particularly for the treatment of allergic conjunctivitis. Other treatment forms have found limited success but each of them has associated disadvantages as well.
Among these treatment forms are vasoconstrictors which take away the red eye component of allergic conjunctivitis. These are limited in their usefulness because once they are discontinued the symptoms reappear in a more severe form. These drugs are unpopular with physicians largely due to this rebound phenomenon. Another drug which has received attention for the treatment of allergic conjunctivitis is disodium cromoglycate, a mast cell stabilizer. Disodium cromoglycate has received regulatory approval for at least one indication; however, it has not proven to be particularly efficacious. Alternatively, glucocorticoids provide relief from the symptoms of hypersensitivity diseases, yet physicians are reluctant to prescribe them because of their side effects.
Researchers and clinicians have long known the importance of both a histaminergic component and a nonhistaminergic component to hypersensitivity diseases. Antihistamines serve as antagonists for the mediators of the histaminergic component; however, it is now generally accepted that to effectively treat these diseases mediators of both components must be suppressed.
A class of compounds known as leukotrienes are known to mediate the nonhistaminergic component, but it was not until the early 1980's that researchers were able to isolate and identify these compounds. Since then a large number of possible leukotriene antagonists have been identified, synthesized, and tested. In Synthesis and Structure--Activity Relationship Studies of a Series of 5-Aryl-4,6-dithianonanedioic Acids and Related Compounds: A Novel Class of Leukotriene Antagonists, J. Med. Chem. 29, 1442-1452, 1986, Perchonock, et al. discuss the leukotriene antagonist activity of the title compounds. Similarly in Communications to the Editor, Journal of Medicinal Chemistry, 30. 959-961, 1987, Gleason, et al. disclose the high affinity leukotriene receptor antagonist activity of 2-hydroxy-3-[(2-carboxymethyl)thio]-3-[-2-(8-phenyloctyl)phenyl]propanoic acid.
When these leukotriene antagonists are tested in animal models they do, in fact, partially block the adverse symptoms associated with hypersensitivity diseases. Furthermore when an antihistamine and a leukotriene antagonist are both administered to sensitized animals, the combination results in a near complete suppression of the symptoms. The test results confirm the theory that if both the histaminergic mediator and nonhistaminergic mediator of the hypersensitivity disease are effectively antagonized, the treatment is more efficacious than blocking a single mediator.
Unfortunately, the above leukotriene receptor antagonists have proven to be extreme tissue irritants. This irritating characteristic is attributed to long chain carboxylate functionalities which give the compounds a detergent like structure. This precludes the utility of these compounds for direct application to the eye, nasal, or bronchial passages. It is further known that the insoluble zinc and poorly soluble calcium salts of leukotriene antagonists are less irritating, because it is believed they do not ionize to form the detergent-like free carboxylate functionalities. However, these salts are not as effective at treating the nonhistaminergic component of hypersensitivity diseases and are incompatible with the soluble antihistamine hydrochlorides which are effective in blocking the histaminergic component. Thus, for purposes of providing a complete formulation for safely and effectively blocking both the histaminergic and nonhistaminergic components of hypersensitivity diseases, the insoluble salts in combination with an antihistamine do not provide a workable solution.
Accordingly, it is an object of the present invention to provide an effective pharmaceutical composition which significantly suppresses the adverse symptoms associated with hypersensitivity diseases.
It is a further object of the present invention to provide a single formulation pharmaceutical composition for effectively treating hypersensitivity diseases without causing irritation of ocular, nasal or lung tissue.
It is an additional object of the present invention to provide pharmaceutical compositions which can be conveniently administered in a variety of delivery forms for the effective treatment of hypersensitivity diseases.